Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis

Abstract

Asthma is on the rise despite intense, ongoing research underscoring the need for new scientific inquiry. In an effort to provide unbiased insight into disease pathogenesis, we took an approach involving expression profiling of lung tissue from mice with experimental asthma. Employing asthma models induced by different allergens and protocols, we identified 6.5% of the tested genome whose expression was altered in an asthmatic lung. Notably, two phenotypically similar models of experimental asthma were shown to have distinct transcript profiles. Genes related to metabolism of basic amino acids, specifically the cationic amino acid transporter 2, arginase I, and arginase II, were particularly prominent among the asthma signature genes. In situ hybridization demonstrated marked staining of arginase I, predominantly in submucosal inflammatory lesions. Arginase activity was increased in allergen-challenged lungs, as demonstrated by increased enzyme activity, and increased levels of putrescine, a downstream product. Lung arginase activity and mRNA expression were strongly induced by IL-4 and IL-13, and were differentially dependent on signal transducer and activator of transcription 6. Analysis of patients with asthma supported the importance of this pathway in human disease. Based on the ability of arginase to regulate generation of NO, polyamines, and collagen, these results provide a basis for pharmacologically targeting arginine metabolism in allergic disorders

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

“…[23][24][25] Chitinase-like proteins YM-1 and YM-2 had been found in crystal forms in the lungs in mouse models of asthma. 23,24 Crystal particles were readily appreciated in the BAL fluid and in the lungs of SHIP-1 −/− mice (see Fig E6, A, in the Online Repository at www.jacionline.org).…”

Nitric oxide paradox in asthma

“…The Arg1 metabolic pathway depletes L-arginine and consequently limits NO synthesis by NOS2 (Wu & Morris 1998). Actually, the final products of Arg 1 pathway are the formation of polyamines and proline that are respectively involved in cell proliferation and collagen formation, which are key features of airway remodeling (Elias et al 1999, Zimmermann et al 2003. Moreover, polyamines down regulate NOS2 activity (Bronte et al 2003).…”

Arginase 1 activity worsens lung‐protective immunity against Streptococcus pneumoniae infection

“…More recent studies in asthmatic patients and animal models of allergic asthma have identified arginase 1 (Arg1) as a key player in the pathophysiology of this disease [3][4][5]. Arg1 is a cytosolic enzyme that hydrolyzes L-arginine to L-ornithine and urea and is constitutively expressed in the liver as a component of the urea cycle [6].…”

“…Previous studies have implicated type 2 helper cell (Th2) cytokines including IL-4, IL-5, and IL-13 released by various leukocyte subsets such as eosinophils, mast cells, lymphocytes, as well as basophils and macrophages in the pathogenesis of allergic asthma [1,3].…”